WO2024026056A2 - Composés hétéroaryle en tant qu'inhibiteurs de l'egfr et leurs utilisations - Google Patents

Composés hétéroaryle en tant qu'inhibiteurs de l'egfr et leurs utilisations Download PDF

Info

Publication number
WO2024026056A2
WO2024026056A2 PCT/US2023/028917 US2023028917W WO2024026056A2 WO 2024026056 A2 WO2024026056 A2 WO 2024026056A2 US 2023028917 W US2023028917 W US 2023028917W WO 2024026056 A2 WO2024026056 A2 WO 2024026056A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino
pyrimidin
pyrrolo
prop
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2023/028917
Other languages
English (en)
Other versions
WO2024026056A3 (fr
Inventor
Jie Fan
Yimin Qian
Wei He
Ke Liu
Pin HUANG
Xiangyan Sun
Jie Su
Ji LIU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Accutar Biotechnology Inc
Original Assignee
Accutar Biotechnology Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Accutar Biotechnology Inc filed Critical Accutar Biotechnology Inc
Publication of WO2024026056A2 publication Critical patent/WO2024026056A2/fr
Publication of WO2024026056A3 publication Critical patent/WO2024026056A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to novel heteroaryl compounds, or pharmaceutically acceptable salts thereof, which possess anti-tumor activity and are accordingly useful in methods of treatment of the human or animal body.
  • the present invention relates to covalent compounds/inhibitors that bind to Epidermal Growth Factor Receptor (EGFR), pharmaceutical compositions comprising the compounds, and methods of use therefor.
  • EGFR Epidermal Growth Factor Receptor
  • Protein kinases are a group of enzymes that regulate diverse, important biological processes including, for example, cell growth, proliferation, survival, invasion and differentiation, organ formation, tissue repair and regeneration. Protein kinases exert their physiological functions through catalyzing the phosphorylation of protein and thereby modulating cellular activities. Because protein kinases have profound effects on cells, their activities are highly regulated. Kinases are turned on or off by phosphorylation (sometimes by autophosphorylation), by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates.
  • EGFR is a transmembrane protein tyrosine kinase member of the erbB receptor family.
  • a growth factor ligand such as epidermal growth factor (EGF)
  • the receptor can homo-dimerize with another EGFR molecule or hetero-dimerize with another family member such as erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4).
  • erbB receptors [5] Homo- and/or hetero-dimerization of erbB receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival. Deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and has been described in many human cancers, including those of the lung, head and neck and breast.
  • the erbB family therefore represents a rational target for anticancer drug development and a number of agents targeting EGFR or erbB2 are now clinically available, including gefitinib (IRESSA®), erlotinib (TARCEVA®) and lapatinib (TYKERB®).
  • gefitinib IRESSA®
  • TARCEVA® erlotinib
  • TYKERB® lapatinib
  • acquired resistance to therapy with gefitinib or erlotinib arises, for example by mutation of the gatekeeper residue T790M, which is reportedly detected in 50% of clinically resistant patients. This mutation is not believed to hinder the binding of gefitinib or erlotinib to EGFR sterically, merely to alter the affinity to ATP to levels comparable to WT EGFR.
  • Exon20 insertion mutations represents the third most common erbB family activating mutations in NSCLC.
  • EGFR exon 20 insertion mutations are collectively representing approximately 4% to 10% of all EGFR mutations. Most of EGFR exon 20 insertion mutations occur near the end of aC-helix after residue Met766, with EGFR D770_N771 insSVD and V769_D770insASV accounting for about 40% of them.
  • erbB2 exon20 insertion mutations occur in a similar prevalence in NSCLC and also in a similar position after residue Met774, with erbB2 A775_G776insYVMA accounting for about 80% of them. See, Jang, J. etal. Angew. Chem. Int. Ed. (2016) Vol. 57(36), 11629-11633.
  • HER2 mutations are reportedly present in about 2-4% of NSCLC (See, Stephens etal. Nature (2004) Vol. 431 , 525-526). The most common mutation is an inframe insertion within exon 20. In 83% of patients having HER2 associated NSCLC, a four amino acid YVMA insertion mutation occurs at codon 775 in exon 20 of HER2. (See, Arcila et al. Clin Cancer Res (2012) Vol. 18, 4910-4918). The exon 20 insertion results in increased HER2 kinase activity and enhanced signaling through downstream pathways, resulting in increased survival, invasiveness, and tumorigenicity (See, Wang et al. Cancer Cell (2006) Vol. 10, 25-38). Tumors harboring the HER2 YVMA mutation are largely resistant to known EGFR inhibitors. (See, Arcila et al. 2012).
  • Such compounds may be expected to be more suitable as therapeutic agents, particularly for the treatment of cancer, due to reduction of toxicology associated with WT EGFR inhibition.
  • toxicologies are known to manifest themselves in humans as skin rashes and/or diarrhea.
  • the inventors have found novel heteroaryl compounds that have high potency against several mutant forms of EGFR and HER2 while at the same showing relatively low inhibition of WT EGFR.
  • the invention provides compounds, compositions and methods for modulating the activity of EGFR.
  • the invention provides compounds which act as inhibitors of EGFR.
  • Xi is chosen from NH, N-CH 3 , S, and CH;
  • X2 is chosen from CH, N, C-CH3, and N-methylpiperazine-4-phenyl
  • X 3 is chosen from C and N;
  • X4 is chosen from N, C-CN, and C-F;
  • R 3 is chosen from H and C1-C5 alkyl
  • W is chosen from alkylamino group, azetidine, methylazetidine, azetidine-
  • X 5 and X 6 are each independently a halogen or a cyano group
  • R 4 is chosen from a C1-C3 alkyl, a C1-C3 alkoxy, , and O;
  • R is chosen from optionally substituted aryls and optionally substituted heteroaryls; wherein Re is H or CH3.
  • the compound of Formula (1 ) may be a compound of
  • the compound of Formula (1 ) may be a compound of
  • the compound of Formula (1 ) may be a compound of
  • the compound of Formula (1 ) may be a compound of
  • W is chosen from
  • R2 is chosen from
  • R2 is chosen from
  • R2 is chosen from
  • R2 is chosen from
  • R2 is chosen from [30]
  • Disclosed are pharmaceutical compositions comprising a compound disclosed herein (e.g., Formula (1 ), Formula (2), Formula (3), Formula (4), Formula (5)) and at least one additional component chosen from pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, and pharmaceutically acceptable excipients.
  • the compound disclosed herein is present in a therapeutically effective amount.
  • a compound disclosed herein e.g., Formula (1 ), Formula (2), Formula (3), Formula (4), Formula (5)
  • the cancer is associated with an EGFR mutation.
  • the cancer is chosen from breast cancer, lung cancer, pancreatic cancer, colon cancer, head and neck cancer, renal cell carcinoma, squamous cell carcinoma, thyroid cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colon cancer.
  • the cancer is breast cancer.
  • the cancer is head and neck cancer.
  • the cancer is sinonasal squamous cell carcinoma.
  • the method further comprises administering to a subject a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (1 ) or a pharmaceutically acceptable salt thereof in combination with another agent.
  • the agent is chosen from gemcitabine, cisplatin, erlotinib, gefitinib, pemetrexed, bevacizumab, cetuximab, trastuzumab, pertuzumab, sorafenib, lapatinib, cobimetinib, selumetinib, and everolimus.
  • the disclosed compounds or the disclosed pharmaceutical compositions and the additional agent are administered concomitantly.
  • the disclosed compounds or the disclosed pharmaceutical compositions and the additional agent are administered sequentially.
  • L47J A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CN is attached through the carbon atom.
  • C1 -C6 alkyl or “C1 -6alkyl” is intended to encompass C1 , C2, 03, C4, 05, 06, C1 -6, C1 -5, C1 -4, C1 -3, C1 -2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • acyl refers to R-C(O)- groups such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)- C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality.
  • acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl.
  • a C4-acyl has three other ring or chain atoms plus carbonyl.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2 to 8 carbon atoms, referred to herein as C2-8alkenyl.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl, 2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1 to 8 carbon atoms, referred to herein as C1 -8alkyl.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1 -propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3 methyl-1 -butyl, 2-methyl-3-butyl, 2,2- dimethyl-1 -propyl, 2-methyl-1 -pentyl, 3 methyl-1 -pentyl, 4-methyl-1 -pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-1 -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-1 -butyl, butyl, isobutyl
  • alkoxy means a straight or branched chain saturated hydrocarbon containing 1 -12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl).
  • alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • alkylene refers to a divalent alkyl radical.
  • Representative examples of C1 -10 alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3- dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2 to 8 carbon atoms, referred to herein as C2-8alkynyl.
  • exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4- methyl-1 -butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.
  • aryl refers to a mono-, bi-, or other multi carbocyclic, aromatic ring system with 5 to 14 ring atoms.
  • the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, heteroaryls, and heterocyclyls.
  • aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • Exemplary aryl groups also include but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “C6-aryl.”
  • cyano refers to CN
  • cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “C3-8cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
  • Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc.
  • cycloalkyl also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.
  • halo or halogen as used herein refer to -F, -Cl, -Br, and/or -I.
  • Haloalkyl means an alkyl group substituted with one or more halogens.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • heteroatoms refers to nitrogen (N), oxygen (O), sulfur (S) or phosphorus (P) atoms, wherein the N, S and P can optionally be oxidized to various oxidation states.
  • heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur.
  • Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls can also be fused to non-aromatic rings.
  • heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as "C2-5heteroaryl.”
  • Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1 ,2,3)- and (1 ,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
  • heteroaryl groups also include, but are not limited to, a bicyclic aromatic ring, wherein the ring comprises 5 to 14 carbon atoms and 1 to 3 heteroatoms, referred to herein as "C5-14heteroaryl.”
  • Representative examples of heteroaryl include, but not limited to, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • heterocycle refers to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur.
  • Heterocycles can be aromatic (heteroaryls) or non-aromatic.
  • Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycly
  • Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
  • Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, o
  • “Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom.
  • the rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • a (C3- 12)spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • “Spiroheterocycloalkyl” or “spiroheterocyclyl” means a spirocycle wherein at least one of the rings is a heterocycle one or more of the carbon atoms can be substituted with a heteroatom (e.g., one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings).
  • One or both of the rings in a spiroheterocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space.
  • Steps or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof.
  • the compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture.
  • stereoisomers can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures.
  • individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.
  • the compound is a racemic mixture of (S)- and (R)- isomers.
  • provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration.
  • the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more.
  • the compound mixture has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
  • the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more.
  • the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more.
  • Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1 ) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well- known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • composition refers to a mixture of at least one compound, such as a compound Formula (1 ), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, with at least one and optionally more than one other pharmaceutically acceptable chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • a compound Formula (1 ) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, with at least one and optionally more than one other pharmaceutically acceptable chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound described herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • compositions in which it is contained refers to pharmaceutically acceptable, as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • carrier refers to chemical compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” is used interchangeably and as is known to those skilled in the art, can be any and all solvents, dispersion media, Coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricant, including sweeteners, flavors, dyes, and the like, and combinations thereof (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
  • prodrugs as used herein represents those prodrugs of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit I risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure.
  • a discussion is provided in Higuchi et al., “Prodrugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • salts refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i
  • Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both.
  • “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • cancer refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body.
  • exemplary cancers include, but are not limited to, breast cancer, lung cancer, pancreatic cancer, colon cancer, head and neck cancer, renal cell carcinoma, squamous cell carcinoma, thyroid cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.
  • subject refers to an animal. Typically, the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a primate.
  • the subject is a human.
  • a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • exon 20 insertion mutation refers to a mutation in which one or more amino acids (preferably 1 to 7, more preferably 1 to 4) are inserted in the exon 20 region of EGFR, and includes, but is not limited to, a mutation in which amino acid sequence SVD (serine, valine, and aspartic acid in this order from the N-terminus) is inserted between the 770th aspartic acid and 771 st asparagine in the exon 20 region (D770_N771 insSVD); a mutation in which amino acid sequence ASV (alanine, serine, and valine in this order from the N-terminus) is inserted between the 769th alanine and 770th aspartic acid in the exon region (A769_D770insASV); and a mutation in which amino acid sequence YVMA (tyrosine, valine, methionine, and alanine in this order from the N-terminus) is inserted between the 775
  • administering means providing a compound of the invention, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or solvate thereof to a subject in need of treatment.
  • the term “combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term “fixed combination” means that the active ingredients, by way of example, a compound of Formula (1 ), or a pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, by way of example, a compound of Formula (1 ) or a pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11 C, 13C, 14C, 15N, 18F, 31 P, 32P, 35S, 36CI and 125I respectively.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H, 13C, and 14C, are present.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Processes using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • Xi is chosen from NH, N-CHa, S, and CH;
  • X 2 is chosen from CH, N, C-CH 3 , and N-methylpiperazine-4-phenyl;
  • X 3 is chosen from C and N;
  • X4 is chosen from N, C-CN, and C-F;
  • R 3 is chosen from H and C1-C5 alkyl
  • W is chosen from alkylamino group, azetidine, methylazetidine, azetidine-3- amine, piperidine, tetrahydropyridine, pyrrolidine, 3-aminopyrolidine, cyclobutylamine, cyclopentylamine, azepane, bicyclic amine, bridge cyclic amine, a spirocyclic amine, and an aryl amine, each of which is optionally substituted with halogen, hydroxyl, C1-C5 alkyl, and C1-C5 alkoxy; and
  • R2 is chosen from wherein:
  • X 5 and X 6 are each independently a halogen or a cyano group
  • R4 is chosen from a CrC 3 alkyl, a CrC 3 alkoxy, , and O, and
  • R5 is chosen from optionally substituted aryls and optionally substituted heteroaryls
  • R6 is H or CH3.
  • the compound of Formula (1 ) may be a compound of Formula (2):
  • the compound of Formula (1 ) may be a compound of
  • the compound of Formula (1 ) may be a compound of
  • the compound of Formula (1 ) may be a compound of
  • W is chosen from
  • R 2 is chosen from
  • R2 is chosen from
  • R2 is chosen from
  • R2 is chosen from
  • R2 is chosen from
  • provided herein is a compound, or pharmaceutically acceptable salt thereof, chosen from the compounds listed in Table 1 .
  • compositions of the present disclosure comprise at least one compound of Formula (1 ), or tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients).
  • the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
  • the carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • a unit-dose formulation for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • Other pharmacologically active substances may also be present including other compounds.
  • the formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one compound of Formula (1), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, which are approximately isotonic with the blood of the intended recipient.
  • These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection.
  • Such preparations may conveniently be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood.
  • Injectable compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of the active compound.
  • Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the active compound i.e., at least one compound of Formula (1), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof
  • the active compound i.e., at least one compound of Formula (1), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof
  • the amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.
  • a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 pg to about
  • a therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used.
  • the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration. Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compositions that exhibit large therapeutic indices are preferable.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 5 o with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • the present disclosure provides a compound of Formula (1 ), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, to be administered to treat cancer in a subject in need thereof.
  • the cancer is associated with an EGFR mutation.
  • the cancer is chosen from breast cancer, lung cancer, pancreatic cancer, colon cancer, head and neck cancer, renal cell carcinoma, squamous cell carcinoma, thyroid cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colon cancer.
  • the cancer is breast cancer.
  • the cancer is head and neck cancer.
  • the cancer is sinonasal squamous cell carcinoma.
  • Also disclosed herein is a method of treating cancer, in a subject in need thereof, comprising administering to said subject a compound of Formula (1 ) (e.g. Formula (2), Formula (3), Formula (4), Formula (5)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (1 ) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (1 ) e.g. Formula (2), Formula (3), Formula (4), Formula (5)
  • a pharmaceutically acceptable salt thereof e.g. Formula (2), Formula (3), Formula (4), Formula (5)
  • a pharmaceutical composition comprising a compound of Formula (1 ) or a pharmaceutically acceptable salt thereof.
  • the method further comprises administering to the subject a compound of Formula (1) or a pharmaceutical composition comprising a compound of Formula (1 ) in combination with another agent.
  • the agent is chosen from gemcitabine, cisplatin, erlotinib, gefitinib, pemetrexed, bevacizumab, cetuximab, trastuzumab, pertuzumab, sorafenib, lapatinib, cobimetinib, selumetinib, and everolimus.
  • the disclosed compounds or the disclosed pharmaceutical compositions and the additional agent are administered concomitantly.
  • the disclosed compounds or the disclosed pharmaceutical compositions and the additional agent are administered sequentially.
  • the cancer is associated with an EGFR or HER2 exon 20 insertion mutation.
  • a compound of Formula (1) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, is administered as a pharmaceutical composition.
  • concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • a compound of Formula (1 ), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof is administered in combination with another therapeutic agent, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • another therapeutic agent e.g., chemotherapy
  • other treatments such as radiation or surgical intervention
  • Also provided herein is a compound of Formula (1 ), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.
  • Also provided herein is a compound of Formula (1), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.
  • Also provided herein is a compound of Formula (1 ), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, for use in the inhibition of EGFR.
  • Also provided herein is a compound of Formula (1 ), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of a disease or disorder associated with an EGFR or HER2 exon 20 insertion mutation.
  • Also provided herein is a use of a compound of Formula (1 ), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of EGFR.
  • Also provided herein is the use of a compound of Formula (1 ), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, as defined herein, in the manufacture of a medicament for the treatment of a disease or disorder associated with an EGFR or HER2 exon 20 insertion mutation.
  • the invention also provides for a method of inhibiting EGFR kinase activity in a cell comprising contacting the cell with an effective amount of an EGFR antagonist.
  • the administered amount is a therapeutically effective amount and the inhibition of EGFR kinase activity further results in the inhibition of the growth of the cell.
  • the cell is a cancer cell.
  • Inhibition of cell proliferation is measured using methods known to those skilled in the art.
  • a convenient assay for measuring cell proliferation is the CellTiter-GloTM Luminescent Cell Viability Assay, which is commercially available from Promega (Madison, Wis.). That assay determines the number of viable cells in culture based on quantitation of ATP present, which is an indication of metabolically active cells. See Crouch et al (1993) J. Immunol. Meth. 160:81-88, U.S. Pat. No. 6,602,677. The assay may be conducted in 96- or 384-well format, making it amenable to automated high-throughput screening (RTS).
  • RTS automated high-throughput screening
  • the assay procedure involves adding a single reagent (CellTiter-Glo® Reagent) directly to cultured cells. This results in cell lysis and generation of a luminescent signal produced by a luciferase reaction.
  • the luminescent signal is proportional to the amount of ATP present, which is directly proportional to the number of viable cells present in culture. Data can be recorded by luminometer or CCD camera imaging device.
  • the luminescence output is expressed as relative light units (RLU). Inhibition of cell proliferation may also be measured using colony formation assays known in the art.
  • the invention provides for methods of treating a condition associated with an EGFR or HER2 exon 20 insertion mutation in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of an EGFR antagonist.
  • the condition is a cell proliferative disease.
  • T reatment of the cell proliferative disorder by administration of an EGFR antagonist results in an observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of cancer cells or absence of the cancer cells; reduction in the tumor size; inhibition of cancer cell infiltration into peripheral organs including the spread of cancer into soft tissue and bone; inhibition of tumor metastasis; inhibition, to some extent, of tumor growth; and/or relief to some extent, one or more of the symptoms associated with the specific cancer; reduced morbidity and mortality, and improvement in quality of life issues.
  • the EGFR antagonist may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. Reduction of these signs or symptoms may also be felt by the patient.
  • the chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques well known in the art. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from about -10° C to about 200° C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10° C to about 200° C over a period that can be, for example, about 1 to about 24 hours; reactions left to run overnight in some embodiments can average a period of about 16 hours.
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. See, e.g., Carey et al. Advanced Organic Chemistry, 3rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2nd Ed., 2005 Hoboken, NJ: J.
  • protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.
  • disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, e.g., from Millipore Sigma or can be readily prepared by those skilled in the art using commonly employed synthetic methodology. [150] The discussion below is offered to illustrate certain of the diverse methods available for making the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that can be used in preparing the compounds provided herein. The skilled artisan will understand that standard atom valencies apply to all compounds disclosed herein in genus or named compound for unless otherwise specified.
  • the claimed compounds can be prepared according to the following schemes.
  • the following schemes represent the general methods used in preparing these compounds.
  • Step 1 Preparation of tert-Butyl 4-(5-amino-4-ethoxycarbonyl-3-thienyl) piperidine- 1 -carboxylate
  • LC-MS demonstrated full consumption of tert-Butyl 4- acetylpiperidine-1 -carboxylate and desired mass was detected.
  • Step 2 Preparation of tert-Butyl 4-(4-hydroxythieno[2,3-d]pyrimidin-5- y I) pi peridine-1 -carboxylate
  • Step 3 Preparation of tert-Butyl 4-(4-chlorothieno[2,3-d]pyrimidin-5-yl)piperidine- 1 -carboxylate
  • Step 1 Preparation of tert-Butyl 4-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6- dihydro-2H-pyridine-1 -carboxylate
  • Step 2 Preparation of ferf-Butyl 4-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5- y I) pi pericline- 1 -carboxylate
  • Step 4 Preparation of 1-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1- yl)prop-2-en-1-one
  • Step 1 Preparation of ferf-Butyl 4-((4,6-dichloropyrimidin-5- yl)(hydroxy)methyl)piperidine-1 -carboxylate
  • Step 2 Preparation of ferf-Butyl 4-(4,6-dichloropyrimidine-5-carbonyl)piperidine- 1 -carboxylate
  • Step 3 Preparation of ferf-Butyl 4-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-3- y I) pi peridine-1 -carboxylate
  • Step 5 Preparation of 1-(4-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-1- yl)prop-2-en-1-one
  • Step 1 Preparation of ferf-Butyl 4-(4-hydroxypyrrolo[2,1-f][1 ,2,4]triazin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate
  • Step 2 Preparation of ferf-Butyl 4-(4-hydroxypyrrolo[2,1-f][1 ,2,4]triazin-5- y I) pi peridine-1 -carboxylate
  • Step 3 Preparation of 4-chloro-5-(piperidin-4-yl)pyrrolo[2,1 -f] [1 ,2,4]triazine
  • TLC (PE/EA 0: 1 ) analysis indicated full consumption of the reactant and one new spot was detected.
  • Step 4 Preparation of 1-(4-(4-chloropyrrolo[2,1-f][1.2.4]triazin-5-yl)pi peridin-1 - yl)prop-2-en-1-one
  • Step 1 Preparation of ferf-Butyl (3-chloro-4-hydroxyphenyl)carbamate
  • reaction mixture was diluted with H 2 O (50 mL) and extracted with EA 90 (30mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product which was further purified by reversed-phase HPLC (MeCN/H 2 O: 100mL/min;B%: 10-35%,35min; 65-
  • Step 2 Preparation of terf-Butyl (4-((2-chloropyridin-4-yl)oxy)-2- fluorophenyl)carbamate
  • Step 1 Preparation of 4-((4-bromothiazol-2-yl)oxy)-2-fluoroaniline
  • Example 1 Preparation of 1-[4-[4-[3-chloro-4-[(3-methyl-2- pyridyl)methoxy]anilino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one, compound 29
  • Step 1 Preparation of 2-[(2-chloro-4-nitro-phenoxy)methyl]-3-methyl-pyridine
  • Step 3 Preparation of 1-[4-[4-[3-chloro-4-[(3-methyl-2-pyridyl)methoxy]anilino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Example 2 Preparation of 1-(4-(4-((3-chloro-4-((3-fluoropyridin-2- yl)methoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one, compound 37
  • Step 1 Preparation of 2-[(2-chloro-4-nitro-phenoxy)methyl]-3-fluoro-pyridine
  • reaction mixture was quenched with HCI (0.5 M, 50 mL) at 10 °C, and then diluted with EA (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with water (20 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give compound 2-[(2-chloro-4-nitro-phenoxy)methyl]-3-fluoro-pyridine (1 g, 3.54 mmol, 89.94% yield) as a yellow solid.
  • Step 3 Preparation of 1-[4-[4-[3-chloro-4-[(3-fluoro-2-pyridyl)methoxy]anilino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Step 1 Preparation of 4-[(2-chloro-4-nitro-phenoxy) methyl] thiazole
  • Step 3 Preparation of 1-[4-[4-[3-chloro-4-(thiazol-4-ylmethoxy)anilino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Step 1 Preparation of 2-[(2-chloro-3-fluoro-4-nitro-phenoxy) methyl] pyridine
  • Step 3 Preparation of 1-[4-[4-[3-chloro-2-fluoro-4-(2-pyridylmethoxy) anilino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Step 3 Preparation of 1 -[4-[4-[3-chloro-4-(pyridazin-3-ylmethoxy) anilino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Step 3 Preparation of 1-[4-[4-[3-chloro-4-(2-pyridylmethoxy)anilino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Step 1 Preparation of 2-[(2-chloro-4-nitro-phenoxy) methyl] pyrazine
  • Step 3 Preparation of 1-[4-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Step 1 Preparation of fert-Butyl N-[3-chloro-4-[[2-(cyclopentanecarbonylamino)-4- pyridyl]oxy]phenyl]carbamate
  • Step 2 Preparation of N-[4-(4-amino-2-chloro-phenoxy)-2-pyridyl] cyclopentanecarboxamide
  • Step 3 Preparation of N-[4-[2-chloro-4-[[5-(1-prop-2-enoyl-4-piperidyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]phenoxy]-2-pyridyl]cyclopentanecarboxamide
  • the crude product was purified by pre-HPLC[column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water( NH4HCO3)-ACN];B%: 34%-64%,10min] and lyophilized to afford N-[4-[2-chloro-4-[[5-(1 -prop-2-enoyl-4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]amino]phenoxy]-2-pyridyl]cyclopentanecarboxamide (4.06 mg, 6.65 umol, 4.98% yield, 96% purity) as a white solid.
  • Step 1 Preparation of fert-Butyl N-[3-chloro-4-[[2-[3-(trifluoromethyl) pyrrolidin-1- yl]-4-pyridyl]oxy]phenyl]carbamate
  • Step 2 Preparation of 3-chloro-4-[[2-[3-(trifluoromethyl)pyrrolidin-1-yl]-4- pyridyl]oxy]aniline
  • Step 3 Preparation of 1-[4-[4-[3-chloro-4-[[2-[3-(trifluoromethyl)pyrrolidin-1-yl]-4- pyridyl]oxy]anilino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • reaction mixture was stirred at 70 °C for 4 hr. LC-MS analysis showed that desired mass was detected.
  • Example 10 Preparation of 1-[4-[4-[4-[[2-(3,3-difluoropyrrolidin-1-yl)-4- pyridyl]oxy]-2-fluoro-anilino]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-piperidyl]prop-2-en-1- one, compound 145
  • Step 1 Preparation of fert-Butyl N-[4-[[2-(3,3-difluoropyrrolidin-1-yl)-4- pyridyl]oxy]-2-fluoro-phenyl]carbamate
  • Step 3 Preparation of 1-[4-[4-[4-[[2-(3,3-difluoropyrrolidin-1-yl)-4-pyridyl]oxy]-2- fluoro-anilino]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-piperidyl]prop-2-en-1-one
  • Example 11 Preparation of 1 -[4-[4-[2-fluoro-4-[[2-(3-hydroxy-3-isopropyl-azetidin- 1 -yl)-4-pyridyl]oxy]anilino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one,5 compound 130
  • Step 1 Preparation of tert-Butyl N-[2-fluoro-4-[[2-(3-hydroxy-3-isopropyl-azetidin-1-yl)-4- pyridyl]oxy]phenyl]carbamate
  • Step 2 Preparation of 1 -[4-(4-amino-3-fluoro-phenoxy)-2-pyridyl]-3-isopropyl- azetidin-3-ol
  • Step 3 Preparation of 1-[4-[4-[2-fluoro-4-[[2-(3-hydroxy-3-isopropyl-azetidin-1-yl)- 4-pyridyl]oxy]anilino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Example 12 Preparation of 1-[4-[4-[4-[[2-(cycloButylamino)-4-pyridyl]oxy]-2- fluoro-anilino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one, compound 109
  • Step 1 Preparation of fert-Butyl N-[4-[[2-(cycloButylamino)-4-pyridyl]oxy]-2- fluoro-phenyl]carbamate
  • Step 3 Preparation of 1-[4-[4-[4-[[2-(cycloButylamino)-4-pyridyl]oxy]-2-fluoro- anilino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1 -one
  • Example 13 Preparation of 1-[4-[4-[2-fluoro-4-[[2-(3-fluoro-3-methyl-pyrrolidin-1- yl)-4-pyridyl]oxy]anilino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one, compound 57
  • Step 1 Preparation of tert-Butyl N-[2-fluoro-4-[[2-(3-fluoro-3-methyl-pyrrolidin-1- yl)-4-pyridyl]oxy]phenyl]carbamate
  • Step 3 Preparation of 1-[4-[4-[2-fluoro-4-[[2-(3-fluoro-3-methyl-pyrrolidin-1-yl)-4- pyridyl]oxy]anilino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Example 14 Preparation of 1 -(4-(4-((2-fluoro-4-((2-(3-methoxy-3-methylazetidin-1 - yl)pyridin-4-yl)oxy)phenyl)amino)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-1-yl)prop-2- en-1 -one, compound 178
  • Step 1 Preparation of tert-Butyl (2-fluoro-4-((2-(3-methoxy-3-methylazetidin-1 - yl)pyridin-4-yl)oxy)phenyl)carbamate
  • reaction mixture was stirred at 80 °C for 4 h. LC-MS analysis showed that desired mass was detected.
  • Step 2 Preparation of 2-fluoro-4-((2-(3-methoxy-3-methylazetidin-1 -yl)pyridin-4- yl)oxy)aniline
  • Step 2 To a solution of terf-Butyl N-[2-fluoro-4-[[2-(3-methoxy-3-methyl-azetidin-1 -yl)-4- pyridyl]oxy]phenyl]carbamate (200 mg, 495.73 umol, 1 eq) in dioxane (1 mL) was added HCI/dioxane (4 M, 3 mL, 24.21 eq) at 0°C for 0.5 h .
  • Step 3 Preparation of 1-(4-(4-((2-fluoro-4-((2-(3-methoxy-3-methylazetidin-1- yl)pyridin-4-yl)oxy)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pipericlin-1-yl)prop-2- en-1-one
  • Example 15 Preparation of 1-(4-(4-((2-fluoro-4-((2-(3-methoxy-3-methylazetidin-1- yl)pyridin-4-yl)oxy)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidin-1-yl)prop-2-en- 1-one, compound 203
  • Example 16 Preparation of 1 -[4-[4-[2-fluoro-4-[4-(5-fluoro-6-methyl-3- pyridyl)thiazol-2-yl]oxy-anilino]-1 H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-piperidyl]prop-2-en-1- one, compound 190
  • Step 1 Preparation of 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine
  • Step 2 Preparation of 2-fluoro-4-[4-(5-fluoro-6-methyl-3-pyridyl)thiazol-2-yl]oxy- aniline
  • Step 3 Preparation of 1-[4-[4-[2-fluoro-4-[4-(5-fluoro-6-methyl-3-pyridyl)thiazol-2- yl]oxy-anilino]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-piperidyl]prop-2-en-1-one
  • Example 17 Preparation of 1-[4-[4-[2-fluoro-4-[4-(5-fluoro-6-methyl-3- pyridyl)thiazol-2-yl]oxy-anilino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]-1 -piperidyl]prop-2-en-1- one, compound 206
  • Step 1 Preparation of N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-5-(4- piperidyl)thieno[2,3-d]pyrimidin-4-amine
  • Step 2 Preparation of 1-[4-[4-[3-chloro-4-(2-pyridylmethoxy) anilino]thieno[2,3- d]pyrimidin-5-yl]-1 -piperidyl]prop-2-en-1 -one
  • Example 19 Preparation of 1-(4-(4-((2-fluoro-4-((2-(2-methylthiazol-4-yl)pyridin-4- yl)oxy)phenyl)amino)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-1 -yl)prop-2-en-1 -one, compound 171
  • Step 2 Preparation of tert-Butyl (2-fluoro-4-((2-(2-methylthiazol-4-yl)pyridin-4- yl)oxy)phenyl)carbamate
  • Step 4 Preparation of 1-(4-(4-((2-fluoro-4-((2-(2-methylthiazol-4-yl)pyridin-4- yl)oxy)phenyl)amino)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-1 -yl)prop-2-en-1 -one
  • Example 20 Preparation of triisopropyl-[2-[6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl]silane
  • Step 1 preparation of tert-butyl (3-chloro-2-fluoro-4-hydroxyphenyl) carbamate
  • Step 2 preparation of 3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)naphthalen-1-ol
  • Step 4 preparation of triisopropyl-[2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 -naphthyl]ethynyl]silane
  • the crude product was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 pm;mobile phase: [water (NH 4 HCOs)-ACN]; B%: 29%-59%,10 min) to give triisopropyl-[2-[6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -naphthyl]ethynyl]silane (110 mg, 21 1 pmol, 8.43% yield, 98.6% purity) as a white solid.
  • Example 21 Preparation of 1 -(4-(4-((3-chloro-4-((2-methylthiazol-4- yl)methoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one (Compound 217)
  • Step 3 1-(4-(4-((3-chloro-4-((2-methylthiazol-4-yl)methoxy)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1 -yl)prop-2-en-1-one
  • Step 1 preparation of 1 -(thiazol-4-yl)ethan-1 -ol
  • Step 2 preparation of 4-(1-(2-chloro-4-nitrophenoxy)ethyl)thiazole
  • Step 4 preparation of 1-(4-(4-((3-chloro-4-(1-(thiazol-4-yl)ethoxy)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1 -yl)prop-2-en-1-one
  • Step 5 preparation of (R)-1-(4-(4-((3-chloro-4-(1 -(thiazol-4- yl)ethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one
  • Step 1 2-[(2-bromo-3-fluoro-4-nitro-phenoxy)methyl]pyridine
  • Step 3 1 -[4-[4-[3-bromo-2-fluoro-4-(2-pyridylmethoxy)anilino]-7H-pyrrolo[2,3- d]pyrimidin-5-yl]-1 -piperidyl]prop-2-en-1 -one
  • Step 1 preparation of 2-((2-chloro-5-fluoro-4-nitrophenoxy)methyl)pyridine
  • AON 150 mL
  • KOH 8.18 g, 146 mmol, 3 eq
  • 2-pyridylmethanol 5.30 g, 48.6 mmol, 4.69 mL, 1 eq
  • Step 3 preparation of 1-(4-(4-((5-chloro-2-fluoro-4-(pyridin-2- ylmethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1 -one
  • Step 1 preparation of 2-[(4-bromo-2,5-dichloro-phenoxy)methyl]pyridine
  • Step 2 preparation of 4-[4-[2,5-dichloro-4-(2-pyridylmethoxy)anilino]-7-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-5-yl]piperidine-1 -carboxylate
  • Step 3 preparation of N-[2,5-dichloro-4-(2-pyridylmethoxy)phenyl]-5-(4-piperidyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 preparation of 1-[4-[4-[2,5-dichloro-4-(2-pyridylmethoxy)anilino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Step 1 preparation of tert-butyl-dimethyl-(thiazol-2-ylmethoxy)silane
  • the reaction mixture was quenched by addition water (100 mL) at 20°C, and then diluted with DCM (10 mL) and extracted with DCM (100 mL * 2). The combined organic layers were washed with water (100 mL * 2), dried over Na 2 SC>4, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 preparation of tert-butyl-[(5-fluorothiazol-2-yl)methoxy]-dimethyl-silane
  • Step 4 preparation of 2-[(2-chloro-4-nitro-phenoxy)methyl]-5-fluoro-thiazole
  • Step 5 preparation of 3-chloro-4-[(5-fluorothiazol-2-yl)methoxy]aniline
  • Step 6 preparation of 1-[4-[4-[3-chloro-4-[(5-fluorothiazol-2-yl)methoxy]anilino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Example 28 Preparation of 1-(4-(4-((3-chloro-4-(thieno[3,2-c]pyridin-6- ylmethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1 -one (Compound 224)
  • Step 1 preparation of methyl thieno[3,2-c]pyridine-6-carboxylate
  • Step 2 preparation of thieno[3,2-c]pyridin-6-ylmethanol
  • Step 4 preparation of 3-chloro-4-(thieno[3,2-c]pyridin-6-ylmethoxy)aniline
  • Step 5 preparation of 1-(4-(4-((3-chloro-4-(thieno[3,2-c]pyridin-6- ylmethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one
  • Step 1 preparation of 2-chloro-4-nitro-1-[3-(trifluoromethyl)phenoxy]benzene
  • Step 3 preparation of 1-[4-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-1-piperidyl]prop-2-en-1-one
  • Step 1 preparation of 1-(3-fluorobenzyl)-1 H-indazol-5-amine
  • Step 2 preparation of 1-(4-(4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1 -yl)prop-2-en-1-one
  • Step 1 preparation of pyridin-2-ylmethan-d2-ol
  • Step 3 preparation of 3-chloro-4-(pyridin-2-ylmethoxy-d2)aniline
  • 2-[(2-chloro-4-nitro-phenoxy)-dideuterio-methyl]pyridine 2.6 g, 9.75 mmol, 1 eq
  • THF 15 mL
  • H2O 15 mL
  • copper 2.6 g, 97.5 mmol, 10 eq
  • NH 4 CI 5.22 g, 97.5 mmol, 10 eq
  • Step 4 preparation of 1-(4-(4-((3-chloro-4-(pyridin-2-ylmethoxy-d2)phenyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one
  • Step 1 preparation of tert-butyl (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)carbamate
  • Step 3 preparation of 1-(4-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1 -yl)prop-2-en-1-one
  • Step 1 preparation of isothiazol-3-ylmethanol
  • Step 4 preparation of 1-(4-(4-((3-chloro-4-(isothiazol-3-ylmethoxy)phenyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one
  • Example 34 Preparation of 1-(4-(4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,2-dimethylpiperidin-1- yl)prop-2-en-1-one (Compound 230) [459] Step 1 : preparation of tert-butyl 3-[4-chloro-7-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-5-yl]-8-azabicyclo[3.2.1]octane-8- carboxylate
  • reaction was carried out vis photo-chemistry platform: To a 15 mL vial equipped with a stir bar was added Aryl halide (0.2 mmol. 1 eq), alkyl iodide (0.4 mmol, 2 eq), lr[dF(CF 3 )ppy]2(dtbpy)(PF 6 ) (0.01 eq), NiCL.dtbbpy (0.015 eq) , TTMSS (1.00 eq), Na2CO 3 (2 eq) in DME (0.1 M) . The vial was sealed and placed under nitrogen was added.
  • Aryl halide 0.2 mmol. 1 eq
  • alkyl iodide 0.4 mmol, 2 eq
  • lr[dF(CF 3 )ppy]2(dtbpy)(PF 6 ) (0.01 eq)
  • NiCL.dtbbpy 0.015 eq
  • TTMSS (1.00 eq
  • the reaction was stirred and irradiated with a 10 W blue LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 14 h.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 2 preparation of tert-butyl (1 R,3r,5S)-3-(4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimiclin- 5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na 2 SO4, filtered, and concentrated under reduced pressure to give a residue.
  • Step 3 preparation of 5-((1 R,3r,5S)-8-azabicyclo[3.2.1 ]octan-3-yl)-N-(3-chloro-4- (pyridin-2-ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 preparation of 1-((1R,3r,5S)-3-(4-((3-chloro-4-(((Z)-2-(methyleneamino)but- 2-en-1 -yl)oxy)phenyl)amino)-7H-pyrrolo[2,3-cl]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octan-8- yl)prop-2-en-1-one
  • Step 1 preparation of tert-butyl (4-((2-(cyclobutanecarboxamido)pyridin-4-yl)oxy)- 2-fluorophenyl)carbamate
  • Step 2 preparation of N-(4-(4-amino-3-fluorophenoxy)pyridin-2- yl)cyclobutanecarboxamide
  • Step 3 preparation of N-(4-(4-((5-(1-acryloylpiperidin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-3-fluorophenoxy)pyridin-2-yl)cyclobutanecarboxamide
  • Step 1 preparation of tert-butyl (4-((2-(cyclopropanecarboxamido)pyridin-4- yl)oxy)-2-fluorophenyl)carbamate
  • Step 2 preparation of N-(4-(4-amino-3-fluorophenoxy)pyridin-2- yl)cyclopropanecarboxamide
  • Step 3 preparation of N-(4-(4-((5-(1-acryloylpiperidin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-3-fluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide
  • reaction mixture was purified by prep-HPLC (TFA conditions) to afford N-(4-(4-((5-(1 -acryloylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3- fluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (32.4 mg, 16.48% yield, 2TFA salts) as a white solid.
  • Example 36 Cellular proliferation assays 0 [482] Generation of HCC827-SVD, HCC827-ASV, and HCC827-YVMA cell lines.
  • HCC827-SVD cell line was generated by first transducing HCC827 cells (ATCC) with lentiviral particles expressing codon-optimized human EGFR exon 20 insertion mutant
  • D770_N771 insSVD D770_N771 insSVD, and then selecting under 5 pg/mL puromycin treatment for a week.
  • the resulting cells were further transduced with lentiviral particles carrying EGFR sgRNA and CAS95 to knockout the endogenous alleles of EGER and then selected under 500 pg/mL hygromycin B treatment for two weeks.
  • the limiting dilution approach was used to subsequently generate the single clone of the HCC827-SVD stable cell line. Endogenous EGFR knockout was confirmed by Sanger sequencing of cell genomic DNA, and expression of exogenous mutant EGFR was verified by Western blot analysis.
  • HCC827-ASV and HCC827-YVMA cell lines were generated in a similar approach as HCC827-SVD, except that HCC827 cells (ATCC) were first transduced with lentiviral particles expressing codon-optimized human EGFR exon 20 insertion mutant V769_D770insASV and human ERBB2 exon20 insertion mutant A775_G776ins YVMA, respectively.
  • HCC827(ATCC), HCC827-SVD, HCC827-ASV, and HCC827-YVMA cells were seeded in 96-well plates at 5000 cells/well in 90 pL of RPMI growth medium containing 10% FBS and 1 % Penicillin Streptomycin.
  • A431 (ATCC) cells were seeded in 96-well plates at 5000 cells/well in 90 pL of DMEM growth medium containing 10% FBS and 1 % Penicillin Streptomycin. Cells were0 incubated at 37°C overnight and then administered with 10pL 10x test compounds prepared in the growth medium at various concentrations. After administration of the compounds, cells were incubated at 37°C for 3 days.
  • the plates were equilibrated at room temperature for approximately 30 minutes. 100 ul of CellTiter-Glo reagent (Promega) was added to each well. The plates were then incubated at room temperature for 10 minutes and5 luminescence was recorded by the EnSight® multimode plate reader (PerkinElmer). Table 7 listed selected compounds in cellular growth assay.
  • B 50 to 200 nmol (including 200 nmol);
  • C 200 to 1000 nmol (including 1000 nmol);

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des composés hétéroaryle et des compositions pharmaceutiques de ceux-ci, qui sont utiles pour inhiber l'EGFR, ainsi que des procédés d'utilisation de tels composés pour le traitement de cancer associé à une mutation d'insertion de l'exon 20 de HER2 ou de l'EGFR.
PCT/US2023/028917 2022-07-29 2023-07-28 Composés hétéroaryle en tant qu'inhibiteurs de l'egfr et leurs utilisations Ceased WO2024026056A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263393470P 2022-07-29 2022-07-29
US63/393,470 2022-07-29

Publications (2)

Publication Number Publication Date
WO2024026056A2 true WO2024026056A2 (fr) 2024-02-01
WO2024026056A3 WO2024026056A3 (fr) 2024-03-14

Family

ID=89707204

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/028917 Ceased WO2024026056A2 (fr) 2022-07-29 2023-07-28 Composés hétéroaryle en tant qu'inhibiteurs de l'egfr et leurs utilisations

Country Status (2)

Country Link
US (1) US20240059698A1 (fr)
WO (1) WO2024026056A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025178977A1 (fr) * 2024-02-20 2025-08-28 Iambic Therapeutics, Inc. Imagerie tep avec des composés inhibiteurs de her2
WO2025178975A1 (fr) * 2024-02-20 2025-08-28 Iambic Therapeutics, Inc. Doses et régimes d'inhibiteurs de her2

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112015023020A2 (pt) * 2013-03-14 2017-07-18 Pfizer combinação de inibidor de egfr t790m e inibidor de egfr para o tratamento de câncer pulmonar de células não-pequenas
WO2016105525A2 (fr) * 2014-12-23 2016-06-30 Dana-Farber Cancer Institute, Inc. Nouvelles pyrimidines en tant qu'inhibiteurs d'egfr et procédés de traitement de troubles
WO2021231400A1 (fr) * 2020-05-12 2021-11-18 Accutar Biotechnology, Inc. Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025178977A1 (fr) * 2024-02-20 2025-08-28 Iambic Therapeutics, Inc. Imagerie tep avec des composés inhibiteurs de her2
WO2025178975A1 (fr) * 2024-02-20 2025-08-28 Iambic Therapeutics, Inc. Doses et régimes d'inhibiteurs de her2

Also Published As

Publication number Publication date
WO2024026056A3 (fr) 2024-03-14
US20240059698A1 (en) 2024-02-22

Similar Documents

Publication Publication Date Title
JP7654071B2 (ja) 複素環スピロ化合物及び使用方法
CN114423756B (zh) 取代的稠合杂芳双环化合物作为激酶抑制剂及其应用
CN104428299B (zh) 5-氮杂吲唑化合物及其使用方法
JP2024532734A (ja) 複素環式化合物及び使用方法
WO2022170043A1 (fr) Composés dérivés de quinazoline en tant qu'inhibiteurs d'egfr et leurs utilisations
CN105732637B (zh) 杂芳化合物及其在药物中的应用
BR112016012262B1 (pt) Acrilamidas heterocíclicas farmaceuticamente ativas e composições para tratar e prevenir condições mediadas por jac
WO2020035052A1 (fr) Composés de pyrazine et leurs utilisations
WO2013024002A1 (fr) Composés de pyrazolo[3,4-c]pyridine et procédés d'utilisation
TW201315726A (zh) 吡唑－４－基－雜環甲醯胺化合物及使用方法
WO2022171034A1 (fr) Composé bicyclique servant d'inhibiteur de hpk1 et son utilisation
CN113966336B (zh) 三环类化合物及其用途
WO2024026056A2 (fr) Composés hétéroaryle en tant qu'inhibiteurs de l'egfr et leurs utilisations
CA3015166C (fr) Composes 6,7-dihydro-5 h-pyrazolo [5,1-b] [1,3]oxazine-2-carboxamide
TW202440111A (zh) 作為ｗｒｎ抑制劑之雜環化合物
CA3142368A1 (fr) Composes heterocycliques utilises en tant qu'inhibiteurs de kinase, compositions comprenant le compose heterocyclique, et leurs procedes d'utilisation
WO2022170164A1 (fr) Sulfonamides ayant des activités d'inhibition de l'egfr et leur utilisation
WO2024211346A1 (fr) Inhibiteurs de pi3k-alpha mutants et leur utilisation en tant que produits pharmaceutiques
US12338248B2 (en) Aminopyrimidine derivatives as cyclin-dependent kinase inhibitors
EP4719394A2 (fr) Inhibiteurs de tyk2
CN119053596A (zh) 作为激酶抑制剂的杂环化合物、其组合物及使用方法
WO2025194057A1 (fr) Composés macrocycliques utilisés en tant que modulateurs de kras et leurs utilisations
WO2025255156A1 (fr) Traitement d'une maladie intestinale inflammatoire
WO2025240582A1 (fr) Composés macrocycliques utilisés en tant que modulateurs de kras et leurs utilisations
WO2025230878A1 (fr) Composés macrocycliques utilisés en tant que modulateurs de kras et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23847372

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23847372

Country of ref document: EP

Kind code of ref document: A2